Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT729IR)

• DTT Name: Voltage-gated calcium channel alpha Cav3.1 (CACNA1G)
• Synonyms: Voltage-gated calcium channel alpha subunit Cav3.1; Voltage-dependent T-type calcium channel; NBR13; Cav3.1c; CACNA1G
• Gene Name: CACNA1G
• DTT Type: Successful target; [1]
• BioChemical Class: Voltage-gated ion channel
• UniProt ID: CAC1G_HUMAN
• TTD ID: T64795
• Sequence:
  MDEEEDGAGAEESGQPRSFMRLNDLSGAGGRPGPGSAEKDPGSADSEAEGLPYPALAPVV
  FFYLSQDSRPRSWCLRTVCNPWFERISMLVILLNCVTLGMFRPCEDIACDSQRCRILQAF
  DDFIFAFFAVEMVVKMVALGIFGKKCYLGDTWNRLDFFIVIAGMLEYSLDLQNVSFSAVR
  TVRVLRPLRAINRVPSMRILVTLLLDTLPMLGNVLLLCFFVFFIFGIVGVQLWAGLLRNR
  CFLPENFSLPLSVDLERYYQTENEDESPFICSQPRENGMRSCRSVPTLRGDGGGGPPCGL
  DYEAYNSSSNTTCVNWNQYYTNCSAGEHNPFKGAINFDNIGYAWIAIFQVITLEGWVDIM
  YFVMDAHSFYNFIYFILLIIVGSFFMINLCLVVIATQFSETKQRESQLMREQRVRFLSNA
  STLASFSEPGSCYEELLKYLVYILRKAARRLAQVSRAAGVRVGLLSSPAPLGGQETQPSS
  SCSRSHRRLSVHHLVHHHHHHHHHYHLGNGTLRAPRASPEIQDRDANGSRRLMLPPPSTP
  ALSGAPPGGAESVHSFYHADCHLEPVRCQAPPPRSPSEASGRTVGSGKVYPTVHTSPPPE
  TLKEKALVEVAASSGPPTLTSLNIPPGPYSSMHKLLETQSTGACQSSCKISSPCLKADSG
  ACGPDSCPYCARAGAGEVELADREMPDSDSEAVYEFTQDAQHSDLRDPHSRRQRSLGPDA
  EPSSVLAFWRLICDTFRKIVDSKYFGRGIMIAILVNTLSMGIEYHEQPEELTNALEISNI
  VFTSLFALEMLLKLLVYGPFGYIKNPYNIFDGVIVVISVWEIVGQQGGGLSVLRTFRLMR
  VLKLVRFLPALQRQLVVLMKTMDNVATFCMLLMLFIFIFSILGMHLFGCKFASERDGDTL
  PDRKNFDSLLWAIVTVFQILTQEDWNKVLYNGMASTSSWAALYFIALMTFGNYVLFNLLV
  AILVEGFQAEEISKREDASGQLSCIQLPVDSQGGDANKSESEPDFFSPSLDGDGDRKKCL
  ALVSLGEHPELRKSLLPPLIIHTAATPMSLPKSTSTGLGEALGPASRRTSSSGSAEPGAA
  HEMKSPPSARSSPHSPWSAASSWTSRRSSRNSLGRAPSLKRRSPSGERRSLLSGEGQESQ
  DEEESSEEERASPAGSDHRHRGSLEREAKSSFDLPDTLQVPGLHRTASGRGSASEHQDCN
  GKSASGRLARALRPDDPPLDGDDADDEGNLSKGERVRAWIRARLPACCLERDSWSAYIFP
  PQSRFRLLCHRIITHKMFDHVVLVIIFLNCITIAMERPKIDPHSAERIFLTLSNYIFTAV
  FLAEMTVKVVALGWCFGEQAYLRSSWNVLDGLLVLISVIDILVSMVSDSGTKILGMLRVL
  RLLRTLRPLRVISRAQGLKLVVETLMSSLKPIGNIVVICCAFFIIFGILGVQLFKGKFFV
  CQGEDTRNITNKSDCAEASYRWVRHKYNFDNLGQALMSLFVLASKDGWVDIMYDGLDAVG
  VDQQPIMNHNPWMLLYFISFLLIVAFFVLNMFVGVVVENFHKCRQHQEEEEARRREEKRL
  RRLEKKRRNLMLDDVIASGSSASAASEAQCKPYYSDYSRFRLLVHHLCTSHYLDLFITGV
  IGLNVVTMAMEHYQQPQILDEALKICNYIFTVIFVLESVFKLVAFGFRRFFQDRWNQLDL
  AIVLLSIMGITLEEIEVNASLPINPTIIRIMRVLRIARVLKLLKMAVGMRALLDTVMQAL
  PQVGNLGLLFMLLFFIFAALGVELFGDLECDETHPCEGLGRHATFRNFGMAFLTLFRVST
  GDNWNGIMKDTLRDCDQESTCYNTVISPIYFVSFVLTAQFVLVNVVIAVLMKHLEESNKE
  AKEEAELEAELELEMKTLSPQPHSPLGSPFLWPGVEGPDSPDSPKPGALHPAAHARSASH
  FSLEHPTDRQLFDTISLLIQGSLEWELKLMDELAGPGGQPSAFPSAPSLGGSDPQIPLAE
  MEALSLTSEIVSEPSCSLALTDDSLPDDMHTLLLSALESNMQPHPTELPGPDLLTVRKSG
  VSRTHSLPNDSYMCRHGSTAEGPLGHRGWGLPKAQSGSVLSVHSQPADTSYILQLPKDAP
  HLLQPHSAPTWGTIPKLPPPGRSPLAQRPLRRQAAIRTDSLDVQGLGSREDLLAEVSGPS
  PPLARAYSFWGQSSTQAQQHSRSHSKISKHMTPPAPCPGPEPNWGKGPPETRSSLELDTE
  LSWISGDLLPPGGQEEPPSPRDLKKCYSVEAQSCQRRPTSWLDEQRRHSIAVSCLDSGSQ
  PHLGTDPSNLGGQPLGGPGSRPKKKLSPPSITIDPPESQGPRTPPSPGICLRRRAPSSDS
  KDPLASGPPDSMAASPSPKKDVLSLSGLSSDPADLDP
• Function: Voltage-sensitive calcium channels (vscc) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release and gene expression.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Calcium signaling pathway (hsa04020)
  Circadian entrainment (hsa04713)
  Type II diabetes mellitus (hsa04930)
• Reactome Pathway: NCAM1 interactions (R-HSA-419037)

Molecular Interaction Atlas (MIA) of This DTT

6 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ethosuximide	DMDZ9LT	Epilepsy	8A60-8A68	Approved	[2]
Methsuximide	DM6L5VO	Absence epilepsy		Approved	[3]
Paramethadione	DMR5ZUP	Absence epilepsy		Approved	[4]
Penfluridol	DMG1DTE	Schizophrenia	6A20	Approved	[5]
Trimethadione	DM0Q8MZ	Absence epilepsy		Approved	[4]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[1]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PD-200390	DMPW28M	Insomnia	7A00-7A0Z	Phase 2	[6]
NGD 94-1	DMM1Y8F	Schizophrenia	6A20	Phase 1	[5]

30 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(-)-(R)-efonidipine	DMV6EMN	Discovery agent	N.A.	Investigative	[7]
Alpha-methyl-alpha-phenylsuccinimide (MPS)	DM892JF	Discovery agent	N.A.	Investigative	[3]
Cis-N,5-dibenzyl-6-oxomorpholine-3-carboxamide	DM75SO4	Discovery agent	N.A.	Investigative	[8]
KKHT-10318	DMAU1SZ	Discovery agent	N.A.	Investigative	[9]
KKHT-10608	DMYT381	Discovery agent	N.A.	Investigative	[9]
KKHT-10609	DMMI1H0	Discovery agent	N.A.	Investigative	[9]
KKHT-10613	DM1H5TO	Discovery agent	N.A.	Investigative	[9]
KKHT-10618	DMW704S	Discovery agent	N.A.	Investigative	[9]
KKHT-11018	DM4F96I	Discovery agent	N.A.	Investigative	[9]
KKHT-20718	DMLB4TU	Discovery agent	N.A.	Investigative	[9]
KKHT-20818	DMP1A3C	Discovery agent	N.A.	Investigative	[9]
KKHT-20918	DMTW4Q1	Discovery agent	N.A.	Investigative	[9]
KYS-05001	DM3MID9	Discovery agent	N.A.	Investigative	[10]
KYS-05040	DM1JU8F	Discovery agent	N.A.	Investigative	[11]
KYS-05041	DMVA6LH	Discovery agent	N.A.	Investigative	[12]
KYS-05042	DMM6G4H	Discovery agent	N.A.	Investigative	[13]
KYS-05050	DMXR3V4	Solid tumour/cancer	2A00-2F9Z	Investigative	[14]
KYS-05055	DMRVOT7	Discovery agent	N.A.	Investigative	[13]
KYS-05056	DMP6S0L	Discovery agent	N.A.	Investigative	[13]
KYS-05057	DM7BYG8	Discovery agent	N.A.	Investigative	[13]
KYS-05064	DM61GPQ	Discovery agent	N.A.	Investigative	[12]
KYS-05065	DMA8LFD	Discovery agent	N.A.	Investigative	[13]
KYS-05070	DMRJQY3	Discovery agent	N.A.	Investigative	[15]
KYS-05071	DM7K5Z3	Discovery agent	N.A.	Investigative	[15]
KYS-05074	DMYRWQ3	Discovery agent	N.A.	Investigative	[15]
KYS-05077	DMHW40F	Discovery agent	N.A.	Investigative	[14]
KYS-05080	DM57BXZ	Discovery agent	N.A.	Investigative	[13]
KYS-05090	DM92RHP	Discovery agent	N.A.	Investigative	[13]
ML218	DM3D21X	Discovery agent	N.A.	Investigative	[16]
Nickel chloride	DMI12Y8	Discovery agent	N.A.	Investigative	[17]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Schizophrenia	6A20	Pre-frontal cortex	3.88E-01	-0.06	-0.18
Schizophrenia	6A20	Superior temporal cortex	9.84E-01	-0.01	-0.03

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Voltage-gated calcium channel subunit alpha Cav3.1 (CACNA1G) DTP Info
• Gene Name: CACNA1G

References

• [1] Mechanism of tissue-selective drug action in the cardiovascular system. Mol Interv. 2005 Apr;5(2):84-93.
• [2] Maladaptive homeostatic plasticity in a rodent model of central pain syndrome: thalamic hyperexcitability after spinothalamic tract lesions. J Neurosci. 2008 Nov 12;28(46):11959-69.
• [3] Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol Pharmacol. 2001 Nov;60(5):1121-32.
• [4] Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss. Hear Res. 2007 Apr;226(1-2):52-60.
• [5] Differential inhibition of T-type calcium channels by neuroleptics. J Neurosci. 2002 Jan 15;22(2):396-403.
• [6] Pfizer. Product Development Pipeline. March 31 2009.
• [7] Identification of R(-)-isomer of efonidipine as a selective blocker of T-type Ca2+ channels. Br J Pharmacol. 2004 Dec;143(8):1050-7.
• [8] Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5244-8.
• [9] Novel T-type calcium channel blockers: dioxoquinazoline carboxamide derivatives. Bioorg Med Chem. 2007 Jan 1;15(1):365-73.
• [10] Discovery of potent T-type calcium channel blocker. Bioorg Med Chem Lett. 2007 Nov 1;17(21):5740-3.
• [11] 3,4-Dihydroquinazoline derivatives as novel selective T-type Ca2+ channel blockers. Bioorg Med Chem Lett. 2004 Jul 5;14(13):3379-84.
• [12] 3D pharmacophore based virtual screening of T-type calcium channel blockers. Bioorg Med Chem. 2007 Jan 15;15(2):1091-105.
• [13] T-type Ca2+ channel blockers suppress the growth of human cancer cells. Bioorg Med Chem Lett. 2008 Jul 15;18(14):3899-901.
• [14] Synthesis and biological evaluation of novel T-type calcium channel blockers. Bioorg Med Chem Lett. 2007 Jan 15;17(2):471-5.
• [15] Growth inhibition of human cancer cells in vitro by T-type calcium channel blockers. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5014-7.
• [16] The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson's Disease. ACS Chem Neurosci. 2011 Dec 21;2(12):730-742.
• [17] T-type calcium channels facilitate insulin secretion by enhancing general excitability in the insulin-secreting beta-cell line, INS-1. Endocrinology. 1997 Sep;138(9):3735-40.